Eph receptor A4 (EphA4) is a member of the receptor tyrosine kinase family and is a molecule regulating postsynaptic morphogenesis. It is known that knockout of EphA4 or expression of an EphA4 dominant-negative mutant causes a reduction in the number of spines, which are small thorn-like protrusions found on dendrites, and also makes their shape slender (Non-patent Document 1). It is generally proposed that the processes of memory and learning are reflected in the number and/or morphology of spines.
Recent studies have clarified that this EphA4 undergoes γ-secretase-mediated cleavage and the cleaved intracellular fragment activates a small GTP-binding protein, Rac, to thereby stimulate spine formation (Patent Documents 1 and 2, and Non-patent Document 2). During the above γ-secretase-mediated cleavage process, full-length EphA4 is first cleaved by another type of protease (MMP (matrix metalloproteinase) family) different from γ-secretase to separate the extracellular domain of EphA4. The region remaining on the cell membrane after MMP-mediated cleavage is then cleaved by γ-secretase. Moreover, it is known that MMP-mediated cleavage of the EphA4 extracellular domain is induced in a neuronal activity-dependent manner (Non-patent Document 2), and it is also kwon that this cleavage reaction of the extracellular domain is a rate-limiting step in this series of cleavage processes.
However, it has not been clarified for what type of disease EphA4 or its extracellular domain serves as a marker.